CN112272554A - 经粘膜的膜组合物及其制备和使用方法 - Google Patents
经粘膜的膜组合物及其制备和使用方法 Download PDFInfo
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- CN112272554A CN112272554A CN201980021894.3A CN201980021894A CN112272554A CN 112272554 A CN112272554 A CN 112272554A CN 201980021894 A CN201980021894 A CN 201980021894A CN 112272554 A CN112272554 A CN 112272554A
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- delivery device
- pharmaceutically active
- oil
- polymer
- polymer film
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Abstract
包含药物活性物的经粘膜的递送装置包含:包含聚合物基质的聚合物膜,其中该膜的pH在约4至约9的范围内;以及置于该聚合物膜的表面上药物活性组合物。该组合物包含至少一种呈颗粒形式的药物活性成分,且其中所述颗粒的平均粒径为约100nm至约5微米,抗结晶剂和pH调节剂,其中药物活性成分的浓度至少是相对于药物活性组合物的总重量的20%w/w。所述递送装置在受试者的口中表现出约5分钟至约30分钟的停留时间,并且当被舌下地放置在舌的下方或被经颊地放置在颊的内衬时,其对粘膜表面基本上是粘膜粘附性的。
Description
相关申请的交叉引用
本申请是要求于2018年2月22日提交的美国临时申请62/633,907的优先权的国际申请,其全部内容通过引用合并于此。
技术领域
本公开的主题涉及经粘膜的(transmucosal)膜组合物,以及制备和使用所述公开的组合物的方法。
背景技术
口服薄膜提供了向受试者施用药物活性物(pharmaceutical active)如药物中间体,生物活性剂,营养制品等的便利方式。但是,这样的膜具有几个缺点。例如,当前的膜不适用于需要高剂量强度,水溶性差,口服生物利用度低和/或易被酶、酸或菌群破坏的药物活性物。特别地,现有技术的膜在与唾液接触时溶解,药物活性物被吞咽,并且药物活性物进入胃肠系统。由于天然体液(例如唾液)往往会迅速洗掉局部应用的药物活性物,因此湿粘膜组织的局部治疗一直存在问题,特别是当需要药物作用迅速起效,生物利用度高并且显著降低代谢产物的血浆峰值浓度的时候。另外,现有技术的膜已经掺入了糊剂作为膜保护剂和作为药物递送系统。但是,此类糊剂的成膜行为和生物粘附性不会持续,并且产品表现的停留时间(residence time)有限。此外,与单层膜相比,包括多层膜的现有技术的膜难以制备并且制备成本更昂贵。因此,提供一种解决现有技术中的缺点的改进的膜装置将是有益的。
发明内容
在本发明的第一方面中,包含药物活性物的单层的,自支撑的,经粘膜的递送装置包括包含聚合物基质的聚合物膜,其中该膜具有置于(disposed)聚合物膜表面上的药物活性组合物。该组合物的pH为约4至约9,并且包含至少一种呈颗粒形式的药物活性成分,其中该颗粒的平均粒径为约100nm至约5微米。该组合物还包含抗结晶剂和pH调节剂。药物活性成分的浓度至少是相对于药物活性组合物的总重量的10%w/w,并且至少是相对于膜组合物表面的30%w/w。所述递送装置在受试者的口中表现出约5分钟至约30分钟的停留时间,并且当被舌下地放置在舌的下方或当被经颊地放置在颊的内衬时,其对粘膜表面基本上是粘膜粘附性的。
在包含药物活性物的经粘膜的递送装置中,基于聚合物膜的总重量,聚合物膜可以包含约80%重量的聚合物基质和约10%重量的渗透促进剂,pH调节缓冲剂,掩味剂和矫味剂中的一种或多种。在本发明的这个方面,药物组合物在表面的pH可以不同于聚合物基质的pH。
包含药物活性物的经粘膜的递送装置可以进一步包含自聚集部分,自组装部分或两者。自聚集或自组装部分的组分可以位于或可以不位于递送装置的相同区域(domain)中。例如,氯化钙可以与海藻酸钠结合使用以产生自组装的屏障凝胶。氯化钙可以是药物活性组合物的组分,或者可以是聚合物膜的组分。类似地,藻酸钠可以是药物活性组合物的组分,或者可以是聚合物膜的组分。
在本发明的第二方面,向有此需要的受试者递送药物活性物的方法包括使受试者的口腔粘膜与含有药物活性物的经粘膜的递送装置接触。在一些实施方案中,受试者是人。
在本发明的第三方面,包含药物活性物的经粘膜的递送装置的制备方法包括将聚合物基质和pH调节剂掺合;溶解掺合物;将掺合物铸塑(casting)成湿的聚合物膜;干燥聚合物膜;将药物活性组合物施加到聚合物膜的表面上,其中组合物的粘度为约1cP至约100cP;然后将聚合物膜与对其施加的药物活性组合物加热,以形成包含药物活性物的经粘膜的递送装置。
在一些实施方案中,聚合物膜的厚度大于所施加的药物活性组合物的厚度(例如,约500%,750%,1000%,2000%,3000%,4000%,5000%,7500%或10000%的药物活性组合物厚度)。
在一些实施方案中,聚合物膜的表面积等于或小于所施加的药物活性组合物的表面积。
在一些实施方案中,药物活性组合物在物理上与聚合物膜是不可分离的。
在一些实施方案中,聚合物膜直接定位成与药物活性组合物相邻。
在一些实施方案中,聚合物膜的局部pH为约4.0至约8.5,并且药物活性组合物的局部pH为约4至约9,并且两个区域的pH不同。
在一些实施方案中,聚合物基质选自水溶性,水溶胀性,和/或水蚀性聚合物,例如(但不限于)羟丙基甲基纤维素(HPMC),甲基纤维素,羟乙基纤维素(HPC),羟丙基纤维素,聚乙烯吡咯烷酮,羧甲基纤维素钠,聚氧化乙烯(PEO),普鲁蓝,海藻酸,海藻酸钠,聚乙二醇,果胶,黄原胶,黄芪胶,瓜尔豆胶,金合欢胶(acacia gum),阿拉伯胶(arabic gum),槐豆胶,结冷胶(gellan gum),聚丙烯酸,与二乙烯基乙二醇(divinyl glycol)交联的聚丙烯酸,甲基丙烯酸甲酯共聚物,羧基乙烯基共聚物,天然和水解淀粉,A和B型明胶,角叉菜胶或其组合。
在一些实施方案中,基于膜的总重量,聚合物膜包含约10至约90%重量的聚合物基质。
在一些实施方案中,渗透促进剂选自一种或多种亲脂性溶剂,表面活性剂,薄荷醇,脂肪酸酯,和多元醇。
在一些实施方案中,缓冲液或pH调节剂选自磷酸盐,乙酸盐,柠檬酸盐,精氨酸,TRIS和组氨酸缓冲液中的一种或多种。
在一些实施方案中,掩味剂选自乙酸纤维素,乙酸丁酸纤维素,乙基纤维素,甲基纤维素及其组合。
在一些实施方案中,矫味剂选自薄荷油,薄荷醇,留兰香油(oil of spearmint),香草(vanilla),肉桂油,冬青油,柠檬油,橙皮油,葡萄油,白柠檬油(lime oil),葡萄柚油,苹果,杏子香精(apricot essence),丁香油,茴香油,豆蔻油,芫荽油,桉树油,小茴香油,柠檬草油,肉豆蔻油及其组合。
在一些实施方案中,药物活性成分或药物活性物是食品或营养生物活性剂。在一些实施方案中,药物活性物选自异黄酮,植物雌激素,番茄红素,花色素苷,表没食子儿茶素没食子酸酯(epigallocatechin gallate),白藜芦醇,车前子种子壳,萝卜硫烷,异黄酮,类黄酮,抗氧化剂或α-亚麻酸中的一种或多种。在一些实施方案中,药物活性物包含一种或多种美容剂,兽药药剂,功能性成分或其组合。
在一些实施方案中,基于组合物的总重量,药物活性组合物还包含约0.1%至约5%重量的自聚集部分,自组装部分,或二者或它们的组分。在一些实施方案中,自聚集或自组装部分选自一种或多种磷脂,胆汁酸,胆盐,纳米血小板结构,或可食用粘土。例如,氯化钙可以与海藻酸钠结合使用以产生自组装的屏障凝胶。药物活性物与自聚集或自组装部分的比例按重量计可为约100∶1至约1∶10。
在一些实施方案中,药物活性组合物药物活性组合物还包含约0.1%至5%重量的氧清除剂。在一些实施方案中,氧清除剂选自一种或多种多元酸,多核酸,蛋白质,多糖,多肽,乙二胺四乙酸(EDTA)及其盐,谷氨酸及其盐,柠檬酸及其盐,膦酸盐,组氨酸,植物螯合肽(phytochelatin),血红蛋白,叶绿素,腐殖酸,转铁蛋白,去铁胺,维生素E醋酸酯,生育酚,及其组合。在一些实施方案中,药物活性物与氧清除剂的比例按重量计为约100:1至约1:10,50:1至约1:5,或20:1至1:1。
在一些实施方案中,药物活性组合物药物活性组合物还包含约0.1%至约5%重量的药物增溶剂。
在一些实施方案中,所述递送装置被配置成当与受试者例如人类的口腔粘膜接触时提供药物活性物的定向递送。
在一些实施方案中,聚合物膜是水可蚀的。在一些实施方案中,聚合物膜基本上不含药物活性物。
在一些实施方案中,递送装置包含一种或多种另外的药物活性组合物,其中所述每种另外的药物活性组合物在物理上与聚合物膜基本上是不可分离的。
在一些实施方案中,递送装置被配置成使得在使用时将聚合物膜放置成与受试者的粘膜组织接触。
在一些实施方案中,基于该层的总重量,第三层包含约5-100%重量的聚合物基质。
附图说明
鉴于附图,将阅读先前的发明内容和以下的发明详述,这些附图示出了当前公开的主题的一些(但不是全部)实施方案。
图1a-1f是包含聚合物膜和药物活性组合物的经粘膜的递送装置的图示。
图2是用于制备过程的示例性过程流程图的示意图。
图3是显示根据实施例5的纳美芬的溶解度随pH变化的照片。
图4是说明不同的pH条件下纳美芬的Merck指数溶解度数据的图。
图5是说明磷酸二氢钠和磷酸氢二钠以不同比例组合的缓冲能力的图。
图6是说明不同比例的甘草酸铵(ammonium glycyrrhinate)-磷酸氢二钠的组合的缓冲能力的图。
图7是在pH为4.2的条件下当使用本文所述的递送性装置的示例性实施方案与常规可得的纳美芬比较时,比较离体猪颊通量的图。
发明详述
引入具有足够细节的当前公开的主题,以提供对更广泛的发明主题的一个或多个特定实施例的理解。这些描述阐述和示例了那些实施例的特征,而没有将本发明的主题限制于明确描述的实施方案和特征。在不脱离当前公开的主题的范围的情况下,基于这些描述的考虑将可能引起额外的和类似的实施方案和特征。
除非另有定义,否则本文中使用的所有技术和科学术语具有与当前公开的主题所属领域的普通技术人员通常理解的相同含义。尽管类似于或等同于本文描述的任何方法,装置和材料都可以用于实践或测试当前公开的主题,现在描述代表性的方法,装置和材料。
根据长期存在的专利法惯例,当在包括权利要求书的主题说明书中使用术语“一个(a)”,“一种(an)”和“所述(the)”时,这些术语是指“一个或多个”。因此,例如,提及“一种膜(a film)”可以包括多个这样的膜,等等。
除非另有说明,否则在说明书和权利要求书中使用的所有表示组分,条件等的数量的数字在任何情况下均应理解为由术语“约”修饰。因此,除非有相反的指示,否则在本说明书和所附权利要求书中列出的数字参数是近似值,其可以根据当前公开的主题寻求获得的期望特性而变化。
如本文所用,术语“约”在指代质量,重量,时间,体积,浓度和/或百分比的值或量时,在一些实施方案中可涵盖具体量+/-20%的变化,在一些实施方案中可涵盖具体量+/-10%的变化,在一些实施方案中可涵盖具体量+/-5%的变化,在一些实施方案中可涵盖具体量+/-1%的变化,在一些实施方案中可涵盖具体量+/-0.5%的变化,在一些实施方案中可涵盖具体量+/-0.1%的变化,因为这样的变化中所公开的包装(package)和方法中是适当的。
本文描述了包含药物活性成分的经粘膜的递送装置,其包括聚合物膜和置于聚合物膜表面上的药物活性组合物。聚合物膜包含聚合物基质。药物活性组合物的pH在约4至约9的范围内。该组合物包含至少一种呈颗粒形式的药物活性成分,其中所述颗粒的平均粒径为约100nm至约5微米。该组合物还包含抗结晶剂和pH调节剂,其中药物活性成分的浓度至少是相对于药物活性组合物的总重量的20%w/w。药物组合物的pH可以与聚合物基质的pH相差大于0.3pH单位。所述递送装置在受试者的口腔、中表现出约5分钟至约30分钟的停留时间,并且当被舌下地放置在舌的下方或当被经颊地放置在颊的内衬时,其对粘膜表面基本上是粘膜粘附性的。
抗结晶剂可包含各种糖醇和二元醇,包括例如山梨醇,甘露醇,木糖醇,异麦芽酮糖醇(isomalt)等中的一种或多种。抗结晶剂可以以活性成分的约10%至40%w/w的量存在于组合物中。例如,抗结晶剂可以以活性成分的约10%,15%,20%,25%,30%,35%或40%w/w的量存在于组合物中。例如,如果活性成分的重量为20mg,并且抗结晶剂的使用量为活性成分的10wt%,则组合物中抗结晶剂的重量为2mg。抗结晶剂可包括一种或多种糖醇的组合,例如山梨醇和甘露醇的组合。当山梨醇和甘露醇一起用作抗结晶剂时,它们每个的量可以变化。例如,山梨醇与甘露醇的量之比可以在1-20∶1(山梨醇:甘露醇)之间变化。因此,山梨醇与甘露醇的比例可以是1:1、5:1、10:1、15:1和/或20:1或在1-20:1范围内的任何比例。
pH调节剂可包含选自磷酸盐缓冲液,乙酸盐缓冲液,柠檬酸盐缓冲液,精氨酸缓冲液,TRIS缓冲液,组氨酸缓冲液,甘草酸铵及其混合物的组分。
药物活性组合物可以进一步包含一种或多种选自下述组成的组:快速溶解的聚合物,水凝胶聚合物,自组装或自聚集部分,分散剂,氧清除剂,药物增溶剂,生物增强剂,矫味剂和掩味剂。快速溶解的聚合物可以包括当被放置在受试者的口中时将在约1分钟至约3分钟内溶解的聚合物。自组装或自聚集部分可包括磷脂,胆汁酸,胆盐,纳米血小板结构和可食用粘土中的一种或多种。此外,可以将二价盐例如钙,镁和锌盐与水凝胶例如海藻酸钠和κ型角叉菜胶(kappa carrageenan)组合使用以形成自组装屏障层。应该理解的是,二价盐可以存在于药物活性组合物中或可以存在于聚合物膜中。相应地,水凝胶可以存在于药物活性组合物中或它可以存在于聚合物膜中。在实施方案中,水凝胶和二价盐之一在药物活性组合物中,而水凝胶和二价盐中的另一个在聚合物膜中,使得当二价盐和水凝胶彼此接触时,它们形成屏障层。自组装或自聚集部分还可包括疏水性自组装部分。
在递送装置中,药物活性成分以颗粒形式直接以20%活性成分重量/活性组合物重量的浓度或更高浓度置于相对薄的聚合物膜的表面上。递送装置可提供高活性生物利用度和快速起效,同时避免首过代谢。活性颗粒的平均直径的尺寸范围可以从小于100纳米到最大5微米。
在一个实施方案中,所述递送装置包含药物活性成分的组合物,其中所述药物活性成分以高浓度(不少于20%w/w)停留在口腔聚合物膜的表面上。聚合物薄膜包含无药物,溶出速率可控的粘膜粘附聚合物,该聚合物可提供控制停留时间约5至约30分钟,提供有效掩盖药物活性成分的味道,和充分的粘膜粘附(当施加在舌头下(舌下)或者受试者口中的颊(颊)内衬时)。药物活性组合物包含药物活性成分的纳米粒或微粒,抗结晶剂,pH调节缓冲剂,结合水凝胶聚合物和快速溶解的聚合物。
当施加在舌头下(舌下地)或者受试者口中的颊(经颊地)内衬时,该递送装置可提供增强的渗透性,快速起效,高活性吸收和减少的代谢产物。
如本文所用的术语“膜”是指薄的柔性材料片,并且旨在涵盖涂覆的膜和膜产品。如本文所用的术语“药物活性物”或“药物活性成分”是指可用于预防和/或治疗受试者的病症的物质或组合物。如本文所用的术语“受试者”是指动物,包括灵长类(猴子,猿,人等)或非灵长类(牛,马,猪,猫,狗,大鼠,小鼠,禽,鱼等)。
图1a示出了单层递送装置5的一个实施方案,其包括聚合物膜和包含药物活性物或其盐的药物活性组合物。特别地,递送装置5包括包含一种或多种聚合物基质的聚合物膜10和包含药物活性物20(或其盐)的药物活性组合物15。重要的是,药物活性组合物15不是自支撑的,并且不能与聚合物膜物理分离。在一些实施方案中,聚合物膜10是自支撑的。在一些实施方案中,聚合物膜被定位成与药物活性组合物相邻或直接相邻。如本文所使用的,术语“相邻”是指彼此直接接触或与在其间的另一层接触的两层的定位。术语“直接相邻”是指彼此接触而在其间没有任何其他层的层。
图1b示出了递送装置5的替代实施方案,其中药物活性组合物是非自支撑的并且包含多种药物活性物20。术语“非自支撑”描述了不能被物理分离以维持其机械完整性的结构。这样的区域可以包括(但不限于)极薄,易碎,离散和/或不连续的区域(region)。图1c和1d示出了递送装置5的替代实施方案,其中药物活性物20停留在被配置为聚合物膜的表面上的屏障基质的药物活性成分15中。如图1d所示,与聚合物膜10相比,药物活性组合物15基本上可以更薄,例如比膜的总厚度至少薄一个数量级。例如,聚合物膜10的厚度可以是药物活性组合物15的厚度的约500%,750%,1000%,2000%,3000%,4000%,5000%,7500%或10000%。在一些实施方案中,递送装置5的药物活性组合物可以在物理上与聚合物膜是不可分离的。类似地,例如,聚合物膜10的表面积可以是药物活性组合物15的表面积的约100%,150%,200%,250%,300%,350%,400%,450%或500%。在一些实施方案中,递送装置5的药物活性组合物可以在物理上与聚合物膜-聚合物膜是不可分离的。
图1e和图1f示出了递送装置5的额外的替代实施方案,其中药物活性组合物具有相对高浓度的药物活性成分。在图1e中,该组合物停留在聚合物膜的表面上,使得该聚合物膜完全限定(circumscribing)药物活性组合物。即,药物组合物不跨聚合物膜的表面延伸至其边缘。在图1f中,药物活性组合物包含将组合物结合到聚合物膜表面的快速溶解的聚合物。如图1e中所示,组合物停留在聚合物膜的表面上,使得聚合物膜完全限定药物活性组合物。如上所述,递送装置5是单层的。术语“单层”是指不包括可以容易被彼此分离的多层的结构,例如通过将区域彼此剥离或推开而彼此分离。因此,所公开的递送装置包括具有聚合物膜的单层,该聚合物膜具有置于其上的药物活性组合物,但是不是多层的层压结构。应当理解的是,与必须连续的层不同,聚合物膜10和药物活性组合物15在结构上可以是离散的或连续的。在一些实施方案中,递送装置包含至少一种在未水合状态下厚度不超过500μm的组分(即,聚合物膜或药物活性组合物)。在一些实施例方案中,递送装置5中的每个组分的厚度为500μm或更小。
聚合物膜10包括一种或多种聚合物基质和任选的一种或多种渗透增强剂,pH调节缓冲液或缓冲剂,掩味剂和/或矫味剂。可以使用任何期望的聚合物基质,包括(但不限于)水溶性,水溶胀性和/或水蚀性聚合物。例如,在一些实施方案中,聚合物基质可以选自羟丙基甲基纤维素(HPMC),甲基纤维素,羟乙基纤维素(HPC),羟丙基纤维素,聚乙烯吡咯烷酮,羧甲基纤维素钠,聚氧化乙烯(PEO),普鲁蓝,海藻酸,海藻酸钠,聚乙二醇,果胶,黄原胶,黄芪胶,瓜尔豆胶,金合欢胶(acacia gum),阿拉伯胶(arabic gum),槐豆胶,结冷胶及其组合,聚丙烯酸, 甲基丙烯酸甲酯共聚物,羧基乙烯基共聚物,天然和水解淀粉,A和B型明胶,角叉菜胶及其组合。
如本文所用,短语“水溶性聚合物”及其变体是指至少部分溶于水,完全或主要溶于水,或吸收水的聚合物。吸收水的聚合物通常被称为水溶胀的聚合物。在一些实施方案中,在聚合物膜10的聚合物基质中使用的材料在室温和/或其他温度(例如超过室温的温度)下可以是水溶性的或水溶胀的。
在一些实施方案中,聚合物基质可以聚合物膜的总重量的约5-100重量%的量存在(例如,基于该区域的总重量,占约5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,或100重量百分比)。聚合物基质提供了自支撑结构和期望的停留时间,以提高生物利用度。
聚合物膜10可任选地包括本领域已知或使用的任何已知的渗透促进剂。术语“渗透促进剂”是指用于增强药物活性物通过皮肤的渗透速率的组分。合适的渗透促进剂可包括(但不限于)亲脂性溶剂,表面活性剂,薄荷醇,脂肪酸酯及其衍生物,多元醇,胆盐,螯合剂,环糊精和壳聚糖及其组合。例如,合适的渗透促进剂可包括(但不限于)壳二糖,壳聚糖,二甲基亚砜(DMSO),亚油酸(LA),肉豆蔻酸异丙酯(IPM),甘氨脱氧胆酸钠(sodiumglycodeoxycholate)(GDC),β-环糊精,油酸(OA)及其组合。在一些实施方案中,渗透促进剂的存在量可以为聚合物膜总重量的约0-5重量%(例如0,0.5,1,1.5,2,2.5,3,3.5,4,4.5或5重量百分比)。
聚合物膜10可以进一步包括一种或多种pH调节缓冲液。可以使用任何能够抵抗pH变化的缓冲液。例如,在一些实施方案中,缓冲液可以选自磷酸盐,乙酸盐,柠檬酸盐,精氨酸,TRIS和组氨酸缓冲液。例如,在一些实施方案中,可以使用柠檬酸缓冲液。在一些实施方案中,缓冲液可以聚合物膜的总重量的约0-5重量%的量存在(例如0,0.5,1,1.5,2,2.5,3,3.5,4,4.5或5重量百分比)。
聚合物膜可任选地包含掩味剂和/或矫味剂以改善膜的气味。术语“掩味剂”是指被添加到组合物中以掩盖一种或多种具有令人不愉快味道的组分的味道的试剂。术语“矫味剂”是指使所公开的膜具有期望的味道或气味的任何添加剂。合适的掩味剂可包括(但不限于)乙酸纤维素,乙酸丁酸纤维素,乙基纤维素,甲基纤维素及其组合。合适的矫味剂可包括(但不限于)天然和人工香料(flavor),例如薄荷油,薄荷醇,留兰香油,香草,肉桂油,冬青油,柠檬油,橙皮油,葡萄油,白柠檬油(lime oil),葡萄柚油,苹果香料油,覆盆子油,草莓油,梨油,蓝莓油,黑莓油,西瓜香料,樱桃油,甘草油,杏子精油,丁香油,茴香油,豆蔻油,芫荽油,桉树油,小茴香油,柠檬草油,肉豆蔻油及其组合。在一些实施方案中,掩味剂和/或矫味剂可以聚合物膜的总重量的约0-5重量百分比的量存在(例如0,0.5,1,1.5,2,2.5,3,3.5,4,4.5或5重量百分比)。
在一些实施方案中,聚合物膜的局部pH为约3.5至约8.5,例如约3.5,4,4.5,5,5.5,6,6.5,7,7.5,8或8.5。在一些实施方案中,药物活性组合物的局部pH在4至9之间,例如在5至8之间,或在6至7之间。在一些实施方案中,递送装置5的pH在3至9之间,例如在4.5和7.5或5和7之间。
药物活性组合物15包含至少一种药物活性成分20或其盐。在一些实施方案中,药物活性物20可以是血管紧张素转化酶抑制剂(例如贝那普利,卡托普利,依那普利,赖诺普利,Moxepril,培哚普利,喹那普利,雷米普利和/或群多普利),成瘾性药物(例如丁丙诺啡,戒酒硫,纳美芬,纳曲酮,大麻二酚,纳呋拉啡(nalfurafine),纳曲酮和/或伐尼克兰(varenicline)),α-1肾上腺素能阻滞剂(例如阿夫唑嗪,多沙唑嗪,哌唑嗪,坦洛新和/或特拉唑嗪),ALS药物(例如利鲁唑),阿尔茨海默病药物(例如多奈哌齐,加兰他敏,利凡斯的明和/或美金刚),过敏,解热和抗生素药物(例如别嘌呤醇,氮斯汀(azelastine),倍氯米松,布地奈德,去氨加压素,氟替卡松,苯肾上腺素(phenylephrine),巴比妥酸盐,甲硝唑,卡马西平,西咪替丁,布洛芬,青霉素,阿莫西林,氯唑西林,双氯西林,替卡西林,phenyloin,奎尼丁,链霉素和/或万古霉素),镇痛药和麻醉药(例如氯胺酮,喷他佐辛(pentozocine),丙泊酚,芬太尼,丁丙诺啡,羟考酮,氢可酮和/或纳布啡);氨来呫诺(amlexanox),苯佐卡因,尿素,过氧化物,制霉菌素,利多卡因和/或毛果芸香碱,血管紧张素II受体阻滞剂(例如坎地沙坦,甲磺酸依普沙坦,奥美沙坦,替米沙汀和/或缬沙坦),抗心律失常药(如腺苷,胺碘酮,阿托品,肾上腺素,美西律,莫雷西嗪,普鲁卡因胺,普罗帕酮,奎尼丁,索他洛尔和/或维拉帕米),抗痉挛和抗胆碱能药(例如莨菪碱,东莨菪碱,达非那星,奥昔布宁,索非那新,托特罗定,格隆铵,莨菪碱,奥昔布宁,丙美卡因,东莨菪碱,异丙嗪,黄酮哌酯,曲司氯铵(trospium)和/或托特罗定),抗惊厥药(例如卡马西平,氯硝西泮,地西泮,乙琥胺,非尔氨酯,普瑞巴林,左乙拉西坦,拉莫三嗪,劳拉西泮,咪达唑仑,奥卡西平,苯巴比妥,噻加宾,妥吡酯和/或丙戊酸),抗抑郁药(如阿塞那平(asenapine),安非他酮(buproprion),丁丙诺啡,西酞普兰,地昔帕明,多塞平,度洛西汀,依他普仑,氟西汀,氟伏沙明,丙米嗪,米氮平,奈法唑酮,去甲替林,去甲替林,舍曲林,曲唑酮和/或文拉法辛),止泻药(例如地芬诺酯,阿托品,loparimide和/或碱式水杨酸铋),抗糖尿病药(例如阿卡波糖,米格列醇,和二甲双胍,glucovance,metaglip,metaglip,罗格列酮,osiglitazone,瑞格列奈,氯磺丙脲,格列美脲,格列本脲,格列吡嗪,妥拉磺脲,甲苯磺丁脲,胰高血糖素,extenatide和/或普兰林肽),抗体和免疫性药物(例如阿达木单抗,阿那白滞素,阿利维A酸,贝卡普勒明,炉甘石,多塞平,氟尿嘧啶,马索罗酚,吡美莫司,他克莫司,金诺芬,硫唑嘌呤,依那西普,羟氯喹,英夫利昔单抗,来氟米特,甲氨蝶呤和/或柳氮磺吡啶),止吐药(例如阿瑞吡坦,多拉司琼,氟哌利多,格拉司琼,甲氧氯普胺,昂丹司琼,丙氯拉嗪,东莨菪碱,异丙嗪和/或曲美苄胺),抗真菌药(例如两性霉素B,阿尼芬净,卡泊芬净,克霉唑氟康唑,氟胞嘧啶,灰黄霉素,伊曲康唑,酮康唑,米卡芬净,制霉菌素,泊沙康唑,特比萘芬,伏立康唑,布替萘芬,环吡酮,克霉唑,enconazole,酮康唑,咪康唑,萘替芬,制霉菌素,奥昔康唑,特比萘芬,布替萘芬,环吡酮,克霉唑,益康唑,酮康唑,咪康唑,萘替芬,制霉菌素,奥昔康唑,特比萘芬,克林霉素,甲硝唑,布康唑,克霉唑,咪康唑,特康唑和噻康唑,和/或托萘酯),抗肝炎(例如阿德福韦,恩替卡韦,拉米夫定,聚乙二醇化干扰素α-2a,聚乙二醇化干扰素α-2b和利巴韦林合剂(rebetron),和/或利巴韦林),抗疱疹药(例如阿昔洛韦,泛昔洛韦,伐昔洛韦,阿昔洛韦,二十二烷醇和/或喷昔洛韦),抗组胺药(例如西替利嗪,地氯雷他定,非索非那定,氯雷他定,氯苯那敏,氯马斯汀,赛庚啶,茶苯海明(dimenhydrinate),苯海拉明,和/或羟嗪),抗高血压(anti-hypertension)(例如贝那普利,卡托普利,依那普利,赖诺普利,莫昔普利,氯沙坦,缬沙坦,阿替洛尔&氯噻酮,比索洛尔,美托洛尔,那多洛尔&苄氟噻嗪,普萘洛尔,噻吗洛尔,氨氯地平&贝那普利,维拉帕米&群多普利,阿米洛利,螺内酯,氨苯蝶啶,可乐定,肼屈嗪,甲基多巴,和/或哌唑嗪&泊利噻嗪),抗高血压药(anti-hypertensive)(例如阿利吉轮,阿利吉伦,依前列醇,非诺多泮,肼屈嗪,米诺地尔,硝普盐(nitroprusside),酚妥拉明和/或曲前列环素),抗流感药(例如磷酸奥司他韦,金刚乙胺和/或扎那米韦),抗疟疾药,抗原生动物药,杀阿米巴药(例如阿托伐醌,氯喹,双碘喹啉,甲氟喹,伯氨喹,乙胺嘧啶,乙胺嘧啶,pyruvium,磺胺多辛和/或奎宁),抗血小板药物(例如阿昔单抗,双嘧达莫/ASA,阿那格雷,西洛他唑,氯吡格雷,双嘧达莫,eptifabatide,噻氯匹定和/或替罗非班),抗精神病药(例如阿立哌唑,氯丙嗪,氯氮平,氟奋乃静,氟哌啶醇,洛沙平,吗茚酮,金刚烷胺,金刚乙胺和美金刚,奥氮平,奋乃静,匹莫齐特,喹硫平,利培酮,硫利达嗪,替沃噻吨,三氟拉嗪,齐拉西酮,和/或锂),抗痉挛药(例如双环胺,donnatal extentabs,丙美卡因,西甲硅油,莨菪碱,利眠宁胶囊(Librax),替加色罗,巴氯芬,carisprodol,环苯扎林,环苯扎林,地西泮,美他沙酮,奥芬那君(orphenadrine),和/或酒石酸麦角胺),抗疱疹药(例如阿昔洛韦,泛昔洛韦,伐昔洛韦,二十二烷醇和/或喷昔洛韦),抗高血压药(例如卡托普利,可乐定,依那普利,艾司洛尔,甲磺酸非诺多潘,肼屈嗪,拉贝洛尔,尼卡地平和/或硝酸甘油),镇咳药/祛痰药(例如苯佐那酯和/或愈创甘油醚),特应性皮炎药物(例如吡美莫司和/或他克莫司),抗焦虑药(例如苯二氮杂类和非苯二氮杂类镇静剂,如阿普唑仑,丁螺环酮,利眠宁,氯氮(chlorazepate),氯硝西泮,地西泮,舒乐安定,eszcpiclone,氟西泮,劳拉西泮,咪达唑仑,奥沙西泮,雷米替胺,替马西泮,三唑仑,扎来普隆和唑吡旦;β阻滞剂,如阿替洛尔,倍他洛尔,比索洛尔,卡维地洛,艾司洛尔,拉贝洛尔,美托洛尔,纳多洛尔,吲哚洛尔,普萘洛尔,索他洛尔和/或噻吗洛尔),胆汁酸螯合剂(例如考来烯胺,考来维仑和/或考来替泊),二膦酸盐(如阿仑膦酸盐,依替膦酸盐,帕米膦酸盐,利塞膦酸盐,替鲁膦酸盐和唑来膦酸,雷洛昔芬和/或特立帕肽),良性前列腺肥大性药物(例如阿夫唑嗪,多沙唑嗪,度他雄胺,非那雄胺,坦洛新和/或特拉唑嗪),钙通道阻滞剂(例如氨氯地平,苄普地尔,地尔硫,非洛地平,伊拉地平,尼卡地平,硝苯地平和/或尼索地平),头孢菌素类(例如头孢羟氨苄,头孢唑林,头孢拉定,头孢氨苄,头孢克洛,头孢替坦,头孢西丁,头孢丙烯,头孢呋辛,头孢呋辛,氯碳头孢,头孢地尼,头孢克肟,头孢哌酮,头孢噻肟,头孢泊肟,头孢他啶,头孢布烯(ceftibuten),头孢唑肟,和/或头孢吡肟),集落刺激因子(例如达依泊汀α(darbepoietin alfa),促红细胞生成素,非格司亭,奥普瑞白介素,聚乙二醇化非格司亭,和/或沙格司亭),皮质类固醇(例如布地奈德,醋酸可的松,地塞米松,氟氢可的松,氢化可的松,甲泼尼龙和泼尼松,aclometasonediproprionate,地奈德,flucinolone acetonide,氢化可的松,二丙酸倍他米松,戊酸倍他米松,氯可托龙匹戊酸酯,去羟米松,氟轻松(fluocinolone acetonide),氟氢缩松,丙酸氟替卡松,chydrocortisone butyrate,戊酸氢化可的松,莫米松糠酸酯,泼尼卡酯,曲安西龙,安西奈德,二丙酸倍他米松增强剂,二丙酸倍他米松,去羟米松,双醋二氟拉松,氟轻松,醋酸氟轻松(fluocinonide),哈西奈德,丙酸氯倍他索,双醋二氟拉松和丙酸卤倍他索,和/或曲安奈德),减充血药(例如苯肾上腺素和/或伪麻黄碱),利尿药(例如乙酰唑胺,阿米洛利,阿米洛利和HCTZ苄氟噻嗪,布美他尼,氯噻嗪,氯噻酮,双氯非那胺,伊普利酮,依他尼酸,呋塞米,氢氯噻嗪,HCTZ/triampterene,氢氟噻嗪,吲达帕胺,醋甲唑胺,甲氯噻嗪,甲氯噻嗪,美托拉宗,泊利噻嗪,螺内酯,螺内酯,HCTZ托塞米,三氯噻嗪,和/或氨苯蝶啶),内分泌药物(例如bromoc cinacalcet cosyntropin,riptine,卡麦角林,降钙素,去氨加压素,亮丙立德,奥曲肽和/或加压素),勃起功能障碍药物(例如西地那非,他达拉非和/或伐地那非),贝特类药(例如氯贝特(clofibrate),非诺贝特和/或吉非贝齐),氟喹诺酮类药物(如环丙沙星,加替沙星,左氧氟沙星,莫西沙星,诺氟沙星和/或氧氟沙星),胃肠道药物(如阿洛司琼,英夫利昔单抗,美沙拉嗪(mesalamine),米索前列醇,新霉素,octreotidev,奥沙拉嗪,奥利司他,sucralafate,加压素别嘌呤醇(vasopressinallopurinol),秋水仙碱,丙磺舒,西咪替丁,法莫替丁,尼扎替丁,雷尼替丁,巴柳氮,布地奈德,英夫利昔单抗,美沙拉嗪,奥沙拉秦,和/或柳氮磺吡啶),干扰素(例如干扰素α-2A,干扰素α-2b,干扰素α-2b和利巴韦林组合包装,干扰素α-N3,干扰素β-1A,干扰素β-1B西洛他唑,和/或己酮可可碱),免疫法(例如B型流感嗜血杆菌和乙型肝炎联合疫苗(Comvax),白喉-破伤风类毒素,甲型肝炎疫苗,乙型肝炎疫苗,流行性感冒疫苗,流感病毒疫苗(Fluzone),莱姆病疫苗,和/或纽莫法{23价肺炎球菌疫苗注射液}(23)),肝素(例如达肝素,达那肝素,依诺肝素,亭扎肝素,和/或磺达肝素),大环内酯类药物(例如阿奇霉素,克拉霉素和/或红霉素),偏头痛药物(例如阿莫曲普坦,依来曲普坦,夫罗曲普坦,那拉曲坦(naratriptan),利扎曲普坦,舒马曲坦,佐米曲普坦,和/或双氢麦角胺),神经肌肉阻滞剂(如阿曲库铵,顺式阿曲库铵,多库铵,米库氯铵,泮库溴铵,罗库溴铵,琥珀胆碱,维库溴铵,米库氯铵,雷帕库铵(rapacuronium),罗库溴铵,琥珀胆碱,阿曲库铵,顺式阿曲库铵,泮库溴铵,维库溴铵,多库铵,哌库溴铵,和/或筒箭毒碱),硝酸盐/酯(例如硝酸异山梨醇酯、单硝酸异山梨糖醇,和/或硝酸甘油),NSAIDs(例如奥湿克,双氯芬酸,依托度酸,吲哚美辛,酮咯酸,舒林酸,tolmentin,二氟尼柳双水杨酯美洛昔康(diflunisal salsalate meloxicam),吡罗昔康,萘丁美酮苯氟布洛芬,布洛芬,酮洛芬,萘普生,奥沙普秦,塞来昔布,罗非昔布,和/或伐地昔布),麻醉剂(opiates)(例如可待因,芬太尼,氢可酮,氢化吗啡酮,哌替啶美沙酮,吗啡,羟考酮,右丙氧芬,曲马朵,paracetomol,丁丙诺啡,布托啡诺,环丁甲羟氢吗啡,喷他佐辛,纳美芬,纳洛酮,ziconotide哌替啶,和/或吗啡),帕金森疾病疗法(例如金刚烷胺、苯扎托品、溴隐亭、恩托卡朋、培高利特、普拉克索、罗匹尼罗、司来吉兰、 托卡朋,和/或苯海索),质子泵抑制剂(例如埃索美拉唑、兰索拉唑、奥美拉唑、泮托拉唑,和/或雷贝拉唑钠),银屑病药疗法(例如,阿维A、阿来西普,地蒽酚,卡泊三醇,依法珠单抗,和/或他扎罗汀),肺部药物(例如异丙托溴铵、tiotropium、沙丁胺醇、双甲苯喘定、左旋沙丁胺醇(levalbuterol)、吡布特罗、间羟异丙肾上腺素、福莫特罗、沙美特罗、倍氯米松、布地奈德、氟尼缩松、氟替卡松、糠酸莫米松、曲安西龙、孟鲁司特、扎鲁司特、色甘酸钠、奈多罗米、乙酰半胱氨酸,和/或氨茶碱/茶碱),HMG COA还原酶抑制剂(例如阿托伐他汀、氟伐他汀、洛伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀,和/或依折麦布(ezetimibe)),兴奋剂(例如托莫西汀、苄甲苯丙胺、咖啡因、dexmethylphenidate、右旋苯丙胺、安非泼拉酮、哌甲酯、莫达非尼、苯异妥英、phendimetrizine、芬特明和西布曲明),四环素类抗生素(例如多西环素、米诺环素,和/或四环素),泌尿外科药(例如戊聚糖、bethanecol,和/或非那吡啶),血管扩张药和血管加压药(例如甲磺酸非诺多泮、肼屈嗪、奈西利肽、硝酸甘油、多巴酚丁胺、多巴胺、肾上腺素、inaminone、米力农、尼古丁、去甲肾上腺素、苯肾上腺素,和/或血管加压素)。
在一些实施方案中,药物活性物可以是食物或营养食品的(nutraceutical)生物活性剂,其选自食物和/或膳食补充剂中负责健康状态变化的一种或多种组成部分(constituent)。例如,药物活性物可以包括(但不限于)植物(例如水果和蔬菜)的组分,例如大豆中发现的异黄酮和植物雌激素,番茄中发现的番茄红素,浆果中发现的类黄酮(例如花青素),绿茶中发现的表没食子儿茶素没食子酸酯(EGCG),红葡萄产品中发现的白藜芦醇,可溶性膳食纤维产品例如车前子种皮,青花菜中的萝卜硫烷,大豆或三叶草中的异黄酮类化合物,类黄酮,抗氧化剂,亚麻籽中的α-亚麻酸,提取物例如人参,大蒜油等。
在一些实施方案中,药物活性物可以是生物活性物(例如植物中的生物活性物,该生物活性物已证明对健康有有益作用(例如植物固醇的降胆固醇的作用)和/或对健康有潜在的有益作用(例如植物化学物质和/或植物营养素))。例如,合适的生物活性物可以包括(但不限于)叶,茎,根,块茎,芽,果实,种子和花朵以及植物来源的食品和饮料(例如茶,咖啡,酒精性饮料)中的植物化学物质。合适的生物活性物可进一步包括在多种植物来源的食物中发现的类黄酮,这些植物来源的食物包括茶,酒,洋葱,苹果和浆果;在茶和咖啡中发现的酚酸;和/或普遍存在于红色、绿色和橙色水果和蔬菜中的类胡萝卜素(其中一些是维生素A的前体)。
药物活性物20可以进一步包括一种或多种美容剂,兽药药剂,功能性成分等。实例包括α-亚油酸(ALA),大麻二酚(CBD),辅酶Q10,姜黄素,软骨素,葡糖胺,谷氨酰胺,大麻籽油,叶黄素,L-肉碱,褪黑激素,蛋氨酸,楝树(neem),ω-3和-6鱼油,圣约翰草(St.John’sWort),矮棕榈,泛醌,维生素,木糖醇或zeazanthin。
药物活性物20可以是固溶体(solid solution),无定形的和/或处于单形态结晶的微粒状态。例如,药物活性物可以以固溶体或基本上均匀的,分散的,无定形的微粒形式存在,其在第一离散区域的表面上停留。如本文所用的术语“固溶体”是指在分子上分散在区域中以形成玻璃态的固体。如本文所用的术语“无定形的”是指具有分子结构的固体材料,该分子结构不具有通过XRD衍射评估的确定的几何形状或晶格图案。无定型的颗粒可以具有玻璃化点,凝胶点,并且可以缺乏结晶晶格结构。在实施方案中,优选无定形颗粒以增加药物活性成分的生物利用度。“单形态结晶状态”是指一种晶格构型的晶态。在实施方案中,本文所用的术语“微粒”是指直径为约0.001-100μm的颗粒。在一些实施方案中,合适的无定形微粒的直径小于约25μm,10μm,5μm,1μm,0.5μm或0.1μm。
在一些实施方案中,药物活性组合物15可包含提供渗透增强特性的一种或多种自聚集和/或自组装部分。如本文所用的术语“自组装”是指分子结构,其在诱导的物理变化和/或触发的相变中排列自己以使系统的总自由能最小化,从而形成热力学稳定的系统。术语“自聚集”是指由于分子聚集成高浓度区域或“富域(rich domain)”的能力而产生的结构。在一些实施方案中,自聚集和/或自组装部分可以以药物活性组合物的总重量的约0-5重量百分比的量存在(例如0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5重量百分比)。自聚集和/或自组装部分提供定向渗透。
在一些实施方案中,合适的自聚集和/或自组装部分可包括(但不限于)磷脂,胆盐,纳米片(nanoplatelets),粘土,极性脂质或其组合。例如,氯化钙可以与海藻酸钠结合使用以产生自组装的屏障凝胶。应当理解的是,氯化钙可以存在于药物活性组合物中或者它可以存在于聚合物膜中。相应地,藻酸钠可以存在于药物活性组合物中或它可以存在于聚合物膜中。在实施方案中,藻酸钠和氯化钙中的一种存在于药物活性组合物中,而藻酸钠和氯化钙中的另一种存在于聚合物膜中,使得当它们彼此接触时,它们形成屏障层。另外,自聚集和/或自组装部分的合适实例可包括磷脂酰胆碱,磷脂酸,磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰甘油,磷脂酰胆碱,磷脂酰丝氨酸,磷脂酰肌醇,磷脂酰肌醇磷酸酯,磷脂酰肌醇二磷酸酯,磷脂酰肌醇三磷酸和/或鞘磷脂。更具体地,自聚集和/或自组装部分可包含1,2-二癸酰基-sn-甘油-3-磷酸胆碱,1,2-二芥酰基(dierucoyl)-sn-甘油-3-磷酸盐(钠盐),1,2-二芥酰基-sn-甘油-3-磷酸胆碱,1,2-二芥酰基-sn-甘油-3-磷酸乙醇胺,1,2-二芥酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(钠盐),1,2-二亚油酰基-sn-甘油-3-磷酸胆碱,1,2-二月桂酰基-sn-甘油-3-磷酸盐(钠盐),1,2-二月桂酰基-sn-甘油-3-磷酸胆碱,1,2-二月桂酰基-sn-甘油-3-磷酸乙醇胺,1,2-二月桂酰基-sn-甘油-3[p磷酸-rac-(1-甘油)(钠盐),1,2-二月桂酰基-sn-甘油-3[磷酸-rac-(1-甘油)(铵盐),1,2-二月桂酰基-sn-甘油-3-磷酸丝氨酸(钠盐),1,2-二肉豆蔻酰基-sn-甘油-3-磷酸盐(钠盐),1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱,1,2-二肉豆蔻酰基-sn-甘油-3-磷酸乙醇胺,1,2-二肉豆蔻酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(钠盐),1,2-二肉豆蔻酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(铵盐),1,2-二肉豆蔻酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(钠/铵盐),1,2-二肉豆蔻酰基-sn-甘油-3-磷酸丝氨酸(钠盐),1,2-二油酰基-sn-甘油-3-磷酸盐(钠盐),1,2-二油酰基-sn-甘油-3-磷酸胆碱,1,2-二油酰基-sn-甘油-3-磷酸乙醇胺,1,2-二油酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(钠盐),1,2-二油酰基-sn-甘油-3-磷酸丝氨酸(钠盐),1,2-二棕榈酰基-sn-甘油-3-磷酸盐(钠盐),1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱,1,2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺,1,2-二棕榈酰基-sn-甘油-3[磷酸-rac-(1-甘油.)(钠盐),1,2-二棕榈酰基-sn-甘油-3[磷酸-rac-(1-甘油)(铵盐),1,2-二棕榈酰基-sn-甘油-3-磷酸丝氨酸(钠盐),1,2-二硬脂酰基-sn-甘油-3-磷酸盐(钠盐),1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱,1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺,1,2-二硬脂酰基-sn-甘油-3[磷酸-rac-(1-甘油...)(钠盐),1,2-二硬脂酰基-sn-甘油-3[磷酸-rac-(1-甘油)铵盐),1,2-二硬脂酰基-sn-甘油-3-磷酸丝氨酸(钠盐),氢化卵PC氢化大豆PC,1-肉豆蔻酰基-sn-甘油-3-磷酸胆碱,1-棕榈酰基-sn-甘油-3-磷酸胆碱,1-硬脂酰基-sn-甘油-3-磷酸胆碱,1-肉豆蔻酰基-2-棕榈酰基-sn-甘油3-磷酸胆碱,1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3–磷酸胆碱,1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3–磷酸胆碱,1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱,1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸乙醇胺,1-棕榈酰基-2-油酰基-sn-甘油-3[磷酸-rac-(1-甘油)](钠盐),1-棕榈酰基-2-硬脂酰基-sn-甘油-3–磷酸胆碱,1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3–磷酸胆碱,1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱,1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱,1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;可食用粘土组分例如钠膨润土,聚磷酸盐,蒙脱石,高岭土,cloisite;胆汁酸和胆盐,其包括胆酸(cholic acid),胆酸钠盐和钙盐,鹅脱氧胆酸,鹅脱氧胆酸钠盐和钙盐,鹅脱氧胆酸,鹅脱氧胆酸钠盐和钙盐,甘氨胆酸,甘氨胆酸钠盐和钙盐,甘草次酸,甘草次酸钠,牛磺胆酸,牛磺胆酸钠盐和钙盐,石胆酸,石胆酸钠盐和钙盐;纳米片,膨润土,cloisite,和/或其组合。
在一些实施方案中,药物活性组合物15可任选地包含一种或多种氧清除剂。如本文所用的术语“氧清除剂”是指可减少或消除不需要的氧化产物的产生的组合物。在一些实施方案中,氧清除剂有效吸收氧。可掺入药物活性组合物15中的合适的氧清除剂可包括(但不限于)抗坏血酸盐,异抗坏血酸盐,鞣质,亚硫酸盐,可氧化的聚合物,多元酸,多核酸,蛋白质,多糖,多肽,乙二胺四乙酸(EDTA)及其盐,有机谷氨酸及其盐,柠檬酸及其盐,膦酸盐,组氨酸,植物螯合肽,血红蛋白,叶绿素,腐殖酸,转铁蛋白,去铁胺,维生素E乙酸酯,生育酚及其组合。在一些实施方案中,氧清除剂可以以药物活性组合物的总重量的约0-5重量百分比的量存在(例如0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5重量百分比)。
在一些实施方案中,药物活性物与氧清除剂的比例为约100:1至约1:10,例如约100:1、90:1、80:1、70:1、60:1、50:1、40:1、30:1、20:1、10:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9或1:10。应当理解的是,氧清除剂可以改善药物活性物或其药学上可接受的盐的氧化稳定性。当存在于公开的膜或层中时,氧清除剂可以进一步改善一种或多种自聚集和/或自组装部分的氧化稳定性。
在一些实施方案中,药物活性组合物15可任选地包含一种或多种药物增溶剂。如本文所用的术语“药物增溶剂”是指形成药物活性物的增溶相的试剂。合适的药物增溶剂可以包括(但不限于)溶剂,油,表面活性剂或磷脂。在一些实施方案中,药物增溶剂可以以药物活性组合物总重量的约0-5重量百分比的量存在(例如,0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5重量百分比)。
在一些实施方案中,递送装置5可包括超过聚合物膜和药物活性组合物。例如,公开的装置可包括聚合物膜,其包含成膜的聚合物基质和任选的一种或多种pH调节剂,掩味剂和/或矫味剂,以提供有效的掩味和/或定向渗透。该装置可以包括第二聚合物膜,该第二聚合物膜包含自组装的磷脂和/或胆盐以提供渗透增强。该装置可以进一步包含药物活性组合物,其包括至少一种药物活性成分或其盐和任选的粘膜粘附性聚合物,pH调节剂和/或氧清除剂,以提供当与口腔粘膜接触放置时的高浓度微环境引起的粘膜粘附和/或高驱动力。
在一些实施方案中,递送装置5可以是粘膜粘附膜。如本文所用的术语“粘膜粘附”是指合成或天然聚合物与生物底物的附着,如Robinson,J R,"Rationale ofBioadhesion/mucoadhesion",in Gurny R.,Junginger,H.E.eds所定义。Bioadhesion:Possibilities and Future Trends,Stuttgart:WissenschaftlicheVerlagsesellschaft,Stuttgart,pages Vol.13page 15(1990),其全部内容通过引用合并于此。当前没有已知的的单层递送装置,其包含聚合物膜和置于其上的药物活性组合物,其中药物活性组合物富含药物活性物,并且当药物活性组合物与口腔粘膜接触放置时,药物活性组合物或聚合物膜中的至少一种可以掩盖味道和增强经粘膜吸收。在一些实施方案中,药物活性组合物或聚合物膜中的至少一种提供增强的经粘膜吸收。在一些实施方案中,当将聚合物膜与受试者的粘膜组织接触放置时,粘膜粘附聚合物提供增强的吸收。
在实施方案中,制备包含药物活性物的经粘膜的递送装置的方法包括将聚合物基质和pH调节剂掺合;溶解掺合物;将掺合物铸塑成湿的聚合物膜;干燥聚合物膜;将药物活性组合物施加到聚合物膜的表面上,其中组合物的粘度为约1cP至约100cP;然后将聚合物膜与对其施加的药物活性组合物加热,以形成包含药物活性物的经粘膜的递送装置。图2提供了制备过程的示例性示意性工艺流程图。
在实施方案中,制备方法可包括形成连续且均匀的单层活性递送装置的方法,该装置包含区域聚合物膜和药物活性组合物,其中聚合物膜和组合物基本上是不可分离的。例如,可以通过使用第一溶剂制备聚合物膜,其包含湿聚合物基质,和一种或多种渗透增强剂,pH调节剂,掩味剂和/或矫味剂,从而构造递送装置。通过铸塑湿聚合物基质形成湿聚合物膜。可以使用干燥设备来干燥湿聚合物基质,并使湿聚合物膜暴露于足以闪蒸第一溶剂的温度,由此干燥聚合物膜为连续单层层合薄膜。然后可以使用第二溶剂制备包含药物活性物的第二湿溶液或悬浮液。通过喷涂,电喷涂,雾化涂覆和/或超薄网状涂覆(ultra-thinweb-coating)工艺将预定量的第二湿溶液施加到第一干聚合物膜的表面上的选定区域上。然后将具有对其施加的药物活性组合物的膜在干燥设备中干燥,并暴露于足以闪蒸第二溶剂的温度,以形成包含药物活性物的递送装置。在一些实施方案中,加热和干燥温度可以在约室温至约250℃的范围内。
在其中递送装置5是经粘膜单层膜装置的实施方案中,通过从合适的供应商(例如Lohmann Therapie Systeme(LTS),Tapemark Inc,Aquestive Therapeutics,或ARx LLC)购买干燥的,无药物的网状涂覆的聚合物基质层压辊(laminate roll)来制备膜递送装置。然后可以使用第二溶剂制备包含药物活性物的第二湿溶液或悬浮液。可以通过喷涂,电喷涂,雾化涂覆和/或超薄网状涂覆工艺将预定量的第二湿溶液或悬浮液施加到干聚合物膜表面的选定区域上。然后可以将具有对其施加的药物活性组合物的湿膜放置在干燥设备中,并暴露于足以闪蒸第二溶剂的加热温度(例如,约室温至250℃)以形成包含药物活性物的递送装置。在一些实施方案中,包含药物活性物的药物活性组合物基本上比聚合物膜薄。
在一些实施方案中,可以通过使用第一溶剂制备第一湿聚合物基质和一种或多种渗透增强剂,pH调节剂,掩味剂和/或矫味剂,从而构造经粘膜的单层递送装置5。可以通过铸塑湿聚合物基质来形成第一湿膜。可以在第二溶剂中制备包含药物活性物20(或其盐)和氧清除剂和/或药物增溶剂的第二湿溶液或悬浮液。然后可以使用喷涂,电喷涂,雾化涂层和/或超薄网状涂覆工艺将预定量的第二湿溶液或悬浮液施加到第一湿聚合物膜的表面上以形成湿的多区域膜。可以将湿的多区域膜放置(deposited)在干燥设备中,并暴露于足以闪蒸第一和第二溶剂的加热温度(例如,约室温至250℃),以形成包含聚合物膜和药物活性组合物的递送装置。在一些实施方案中,药物活性组合物基本上比聚合物膜薄。
在一些实施方案中,可以通过使用第一溶剂制备第一湿聚合物基质和一种或多种渗透增强剂,pH调节剂,掩味剂,自聚集部分(例如膨润土)和/或矫味剂,从而构造递送装置5。可以通过浇铸湿聚合物基质来形成第一湿膜。可以将第一湿聚合物基质放置在干燥器设备中,并暴露于足以闪蒸第一溶剂的温度下,以形成铸塑为连续单层层合薄膜的第一干膜。然后可以在第二溶剂中制备第二湿溶液或悬浮液,其包含药物活性物20(或其盐)和任选的氧清除剂和/或药物增溶剂(例如自组装磷脂和/或胆盐)。可以使用喷涂,电喷涂,雾化涂覆和/或超薄网状涂覆工艺将预定量的第二湿溶液或悬浮液施加到聚合物膜的表面上(或表面的选定区域上)。可以将湿的多区域膜放置在干燥设备中,并暴露于足以闪蒸第一和/或第二溶剂的加热温度(例如,大约室温至250℃)以形成干燥的连续单层包含药物活性物的递送装置。在一些实施方案中,药物活性组合物基本上比聚合物膜薄。
递送装置5可以以任何期望的形式构造,例如(但不限于)膜带,片,盘,晶片等。递送装置可具有任何期望的厚度,例如约50至约500μm,尽管具有更大或更小的厚度的膜也包括在当前公开的主题的范围内。可以将递送装置5构造成任何期望的形状,例如矩形,正方形,圆形,三角形,抽象物(abstract)等。应当理解的是递送装置5可以具有适合于预期用途的任何期望的厚度和/或尺寸。例如,递送装置可以是单剂量大小的单元,其将被放置到使用者的口腔中。
递送装置5可以由连续的膜卷(roll of film)形成,或者可以定尺寸为期望的长度和宽度。
含有药物活性物的经粘膜的递送装置的示例性实施方案包括递送装置,其中药物活性成分包含纳美芬。包含纳美芬的递送装置可以用于治疗结节性痒疹(PN)和与慢性肾脏病相关的瘙痒疹(CKD-aP)。结节性痒疹是一种慢性皮肤病症,其特征是皮肤上严重瘙痒性结。患有结节性痒疹的个体通常有多发性表皮剥脱病损。这种病症在患有慢性肾脏疾病的患者中很常见,这会导致“抓挠-瘙痒”周期,形成离散的,结节性的,表皮剥脱的,色素沉着过度的/紫癜的肿块,表面有鳞屑或结痂。考虑了变化的剂量强度。例如,剂量强度可以包括在药物活性组合物中的1mg,2mg,3mg,4mg,5mg,6mg,7mg,8mg,9mg,10mg,11mg,12mg,13mg,14mg,15mg,16mg,17mg,18mg,19mg,20mg,25mg,30mg,35mg,37.5mg,40mg,50mg,60mg,75mg,100mg,150mg纳美芬。
预期用于组合物中的赋形剂已用于现存的商业产品中,并且在FDA的非活性成分数据库中。所述赋形剂包括:羟丙基甲基纤维素USP,聚氧化乙烯NF,羧甲基纤维素钠NF,糖精钠USP,山梨糖醇NF,蓝色FD&C染料,薄荷油NF,磷酸二氢钠USP,磷酸氢二钠USP,PEG400NF,甘油USP,丙二醇NF,甘草酸铵NF,O2,乙醇NF和水NF。
可以将示例性膜包装在2.5英寸宽和3.5英寸长的白色不透明,单独密封的V形袋中。每个袋可包括1块SteriFlex 301箔,该箔已热封到1块301P箔上。膜可以在室温下于25℃下保存。热封宽度可以是0.25英寸,这需要0.6到3.0磅之间的剥离强度才能打开袋子。通过在热封下方用剪刀剪开袋。
从袋中取出后,可通过舌下地(舌下)施用该递送装置。
与常规口腔膜制备不同,活性成分未掺入聚合物膜的基质内或递送装置内。相反,将药物溶液喷涂或直接沉积在聚合物膜的表面上,该聚合物膜中未掺入活性物。在其中溶解活性成分的溶剂快速蒸发之后(在药物活性组合物中),发生组成猝灭,由此使活性物在粘合聚合物(binding polymer)中发生相分离而不形成核。
产生纳米颗粒的典型方法是复杂,昂贵和耗时的。典型的过程是多步骤的,并且经常受到颗粒附聚问题的挑战。所描述的方法通过使用一步法来克服这些问题,其中使用防止在施加过程中药物活性物附聚的施用方法产生纳米粒或微粒,然后将其随后就位锁定在聚合物膜的表面上。
有利地,所描述的方法可以成比例的用于商业用途。提供单步制备大大降低了商品成本。此外,所描述的方法为制备过程提供了有利的均匀性和一致性。该制备方法始终生产剂量在目标剂量的90%-110%之内的递送装置。例如,对于3.75mg的目标剂量,使用所述方法制备的递送装置将具有在3.375mg至4.125mg范围内的剂量。制备过程中的均匀性和一致性提供了生产时间和原材料的使用效率,从而节省了成本,提高了盈利能力并缩短了生产时间。
在使用中,可以将包含药物活性成分的所述递送装置施用于需要其的受试者。例如,所公开的膜可以被与受试者的口腔粘膜接触放置。应当理解的是,制备单层生物相容性膜对于提供快速的经粘膜的吸收作用是至关重要的,其中药物活性物以高浓度以分子状态存在于紧邻粘膜的微环境中。为了使这种系统起作用,药物活性物的溶解速率必须明显快于基质的溶解速率。此外,药物作为离散的高浓度区域停留的这种装置将使流向药物活性物的唾液流最小化(类似于但不同于双层膜)。
所公开的膜可以提供药物活性物的有效掩味,定向渗透,快速吸收和/或增强的生物利用度的作用。在一些实施方案中,第一离散区域包含成膜聚合物基质,pH调节剂,掩味剂,自组装磷脂或胆盐和/或矫味剂以提供有效的掩味和/或定向渗透。在一些实施方案中,与包含药物活性物5的第二离散区域相比,第一离散膜区域具有较慢的溶解速率。
有利地,所公开的单层膜结构包括多个离散区域,其中至少一个离散区域富含药物活性物或其盐。
此外,本发明公开的主题包括包含多个离散区域的单层膜结构,其中至少一个区域富含药物活性物或其盐,并且其中药物活性物以固溶体,无定形,或单形态结晶微粒的形式存在。
所公开的单层膜结构进一步包括至少一个离散区域,当将包含药物活性物的离散区域与受试者的口腔粘膜接触放置时,其提供有效的掩味和/或增强的经粘膜吸收。
实施例
已经包括以下实施例以为本领域的普通技术人员提供指导,以实施本公开主题的代表性实施方案。鉴于本公开和本领域技术人员的一般水平,本领域技术人员可以理解,以下实施例仅是示例性的,并且在不脱离本公开主题的范围的情况下可以采用许多改变,修改和变更。
预测性实施例1
构造膜组合物1
膜组合物1将通过制备聚合物与一种或多种选自羟甲基纤维素USP,971P NF,甘露醇NF,糖精钠,磷脂酰胆碱,甘油二油酸酯,着色剂,柠檬酸和橙香料(orange flavor)的赋形剂的掺合物来构造。该掺合物将被溶解,并且其组分分散在水中。然后将掺合物在隔离衬里表面上铸塑成规定厚度的湿膜,例如在对流烘炉中于60℃进行20分钟的受控干燥后,膜将被干燥,且磷脂酰胆碱和甘油二油酸酯将在膜表面自组装。结果,将构造具有两个区域的单层膜。通过喷涂雾化将药物活性物(例如东莨菪碱)和pH调节剂(例如柠檬酸)掺入聚合物膜的表面上,在膜的表面上产生第三区域。膜产品将被切成约1.14cm2的单个盘单元装置。
预测性实施例2
构造膜组合物2
膜组合物2将通过制备聚合物和一种或多种选自羟丙基甲基纤维素USP,971P NF,甘露醇NF,糖精钠NF,磷脂酰甘油,着色剂和薄荷香料(peppermint flavor)的赋形剂的掺合物来构造。该掺合物将被溶解,并且其分散在水中。然后将掺合物在隔离衬里表面上铸塑成规定厚度的湿膜,例如在对流烘炉中于160℃进行12分钟的受控干燥后,将构造包含聚合物膜的膜。将预定量的药物活性剂(例如阿塞那平HCl USP,971P NF,聚卡波非AA-1NF和柠檬酸钠NF)喷涂在聚合物膜的表面上,从而形成药物活性组合物。药物活性组合物代表预定量的作为在聚合物膜表面上的喷涂物(spray)沉积的药物活性物(阿塞那平HCl USP)。膜产品将被切成2.6cm2的单个盘单元装置。
预测性实施例3
构造膜组合物3
膜组合物3将通过制备聚合物和一种或多种选自羟丙基甲基纤维素USP,糖精钠NF,苯甲酸钠NF,FD&C着色剂,柠檬酸,甘露醇NF,和柠檬薄荷香料的赋形剂的掺合物来构造。该掺合物将被溶解,并且其分散在水中。然后将掺合物在隔离衬里表面上铸塑成规定厚度的湿膜,例如在对流烘炉中于120℃进行15分钟的受控干燥后,将构造包含聚合物膜的膜。将预定量的药物活性物作为在聚合物膜的表面上的喷涂物沉积,从而形成药物活性组合物。药物活性物将包含曲前列尼USP,维生素E乙酸酯,聚卡波非AA-1NF,和柠檬酸钠NF。膜产品将被切成2.6cm2的单个盘单元装置。
预测性实施例4
构造膜组合物4
通过生产羟丙基甲基纤维素USP,糖精钠NF,磷脂酰胆碱,维生素E乙酸酯,苯甲酸钠NF,FD&C着色剂,麦芽糖醇80/55,柠檬香料和水的湿聚合物掺合物,可以制得具有两个区域的单层膜。将聚合物掺合物以预定的厚度铸塑到湿厚度约为1mm的隔离衬里上,然后在60℃下干燥30分钟,以形成第一干膜。
将制备第二湿药溶液,其包含预定量的药物活性物,纳美芬HCl USP,维生素E乙酸酯,聚卡波非AA-1NF,柠檬酸和柠檬酸钠NF。所得膜将在对流烘炉中于95℃干燥10分钟。膜产品将被切成1.14cm2的单个盘单元装置。
实施例5
药物活性成分溶解度
为了确定示例性药物活性成分的溶解度,在100mg/mL的五个不同pH条件下(pH2.25、4.0、6.8、8.0、9.6)进行了视觉评估研究(模拟浊点)。示例性的药物活性成分是纳美芬(表示为游离碱)。进行实验以确定浊点。图3是在五个测试的pH值下样品的照片。如图所示,图3说明了各种测试pH值下的浊点。从左到右,水性介质的pH值增加。在6.8(小瓶3A)处观察到的浊点证明了溶解度拐点pH,这与示例性药物活性成分在Merck Index,第19版,(2001)中呈现出的数据一致。Merck Index中提供的溶解度数据图表如图4所示。
实施例6
药物活性成分溶解度
进行测试以评估示例性药物活性成分在增强溶解度的极性溶剂和增溶剂中的溶解度。示例性活性物是100mg/mL的纳美芬盐酸盐一水化物。考虑的不同溶剂包括乙醇,丙二醇,甘油,甲醇和水。表1显示了溶解度评估观察结果。
表1.纳美芬在极性溶剂中的溶解度
此外,使用溶剂系统的不同组合评估了纳美芬在不同浓度下的溶解度。溶剂系统包括极性溶剂与不同表面活性剂的组合。示例性表面活性剂包括:吐温20,吐温80、34/44,HS 15,NF,M2125 CS和M1944CS。
表2显示了溶解度评估观察结果。
实施例7
用于药物活性组合物的缓冲剂
进行测试以评价用于将示例性药物活性组合物的pH控制在5.75至9的缓冲液组合。测试了不同浓度比的磷酸二氢钠和磷酸氢二钠的组合。结果如图5所示。
此外,已确定可以将更传统地用作掩味剂的甘草酸铵与磷酸氢二钠作为合适的缓冲剂在6.25至9的缓冲范围内结合使用。图6是显示示例性缓冲剂组合的pH控制的图,该组合包括变化比例的甘草铵和磷酸氢二钠的组合。可以看出,这些组合在相对较高的pH条件下提供了pH控制。甘草酸铵和磷酸氢二钠的缓冲液组合可用于控制较高pH条件(例如7.5或更高)下的pH。
实施例8
考虑用于药物活性组合物的赋形剂
考虑并评估了包括不同成分的示例性组合物。考虑了用于减少和/或防止口服膜剂型中活性物的晶核生成和生长的各种抗结晶剂。另外,还考虑了具有合适的粘膜粘附和pH属性的影响在口中的停留时间的赋形剂。停留时间可以在约5分钟至约30分钟的范围内,例如约8分钟至约10分钟。另外,测试了使海藻酸钠瞬间胶凝从而防止活性物迁移到聚合物膜中的二价钙离子。此外,测试了不同的矫味剂和/或掩味剂。
制备了具有不同选择的聚合物,分子量和聚合物比例的示例性制剂。另外,制备了具有不同选择和数量的矫味剂,着色剂,掩味剂,甜味剂,增塑剂,湿润剂,生物增强剂和缓冲剂的示例性制剂。
表3提供了示例性组合物的组分,量和组成关系的小结。
使用不同药物浓度的其他示例性组合物如下表4所示。
实施例9
溶出度和离体渗透测试
在不同的pH条件下(包括pH值为5.75、7.0和8.3)测试溶出度和离体渗透。测试了包含纳美芬盐酸一水化物的示例性递送装置。除了pH值变化外,递送装置的组成相同。与纳美芬片剂在pH值为4.2时相比,测试了在不同pH下的递送装置。对于每个示例性装置和参考片剂,测试了两个样品。根据EMA/CHMP/QWP/608924/2014和OECD-Guideline 28和428Guideline(用于化学品测试,体外皮肤吸收方法),考虑了离体猪颊粘膜并在颊粘膜Franz细胞中使用。结果如图7所示。从图7可以看出,每个递送装置的渗透均高于参考值,其中pH值为7.0的递送装置具有最高的渗透。
Claims (43)
1.包含药物活性物的经粘膜的递送装置,其包含:
a)包含聚合物基质的聚合物膜,和;
b)置于聚合物膜表面上的药物活性组合物,其中所述组合物的pH在约4至约9的范围内,且其中所述组合物包含:
-至少一种颗粒形式的药物活性成分,且其中所述颗粒的平均粒径为约100nm至约5微米
-抗结晶剂
-pH调节剂,其中药物活性成分的浓度至少是相对于药物活性组合物总重量的20%w/w,和
-粘合聚合物,
其中所述递送装置在受试者的口中表现出约5分钟至约30分钟的停留时间,并且当被舌下地放置在舌的下方或被经颊地放置在颊的内衬时,其对粘膜表面基本上是粘膜粘附性的。
2.权利要求1所述的递送装置,其中所述药物活性组合物进一步包含胶凝剂,并且其中与同样的成分被受试者口服施用相比,其中所述的活性成分在小于约90min内达到受试者的最大血浆浓度并且具有大于125%的生物利用度。
3.权利要求1所述的递送装置,其中所述抗结晶剂包含选自由山梨醇,甘露醇和木糖醇组成的组中的组分。
4.权利要求1所述的递送装置,其中所述pH调节剂包含选自由磷酸盐缓冲液,乙酸盐缓冲液,柠檬酸盐缓冲液,精氨酸缓冲液,TRIS缓冲液,组氨酸缓冲液,甘草酸铵及其混合物组成的组中的组分。
5.权利要求1所述的递送装置,其中所述药物活性组合物进一步包含一种或多种选自快速溶解的聚合物,自组装或自聚集部分或其组分,分散剂,氧清除剂,药物增溶剂,生物增强剂,矫味剂和掩味剂组成的组中的组分。
6.权利要求5所述的递送装置,其中所述快速溶解的聚合物包含当放置在受试者的口中时将在约1分钟至约3分钟内溶解的聚合物。
7.权利要求5所述的递送装置,其中所述自组装或自聚集部分选自磷脂,胆汁酸,胆盐,纳米血小板结构,与离子水凝胶聚合物结合的二价盐,和可食用粘土中的一种或多种。
8.权利要求7所述的递送装置,其中所述自组装或自聚集部分包含疏水性自组装部分。
10.权利要求7所述的递送装置,其中所述二价盐是氯化钙,柠檬酸钙,乳酸钙或其他基于Ca++、Mg++、Zn++的GRAS可接受的盐,并且所述的离子水凝胶聚合物是海藻酸钠或κ型角叉菜胶及其混合物。
11.权利要求5所述的递送装置,其中所述药物增溶剂包含选自由乙醇NF,丙二醇USP,甘油USP,甲醇,水及其混合物组成的组中的组分。
12.权利要求5所述的递送装置,其中所述分散剂和所述药物增溶剂包含用于所述药物活性成分的溶剂系统,并且所述的溶剂系统包含一种或多种分散剂和一种或多种增溶剂的混合物。
13.权利要求5所述的递送装置,其中所述溶剂系统包含不同比例的乙醇,水,丙二醇,吐温20,吐温80,甘油,Gelucire,Labrafil M2125 CS,和/或M1944 CS中的一种或多种。
14.权利要求5所述的递送装置,其中所述氧清除剂选自一种或多种多元酸,多核酸,蛋白质,多糖,多肽,乙二胺四乙酸(EDTA)及其盐,谷氨酸及其盐,柠檬酸及其盐,膦酸盐,组氨酸,植物螯合肽,血红蛋白,叶绿素,腐殖酸,转铁蛋白,去铁胺,维生素E乙酸酯,生育酚及其组合。
15.权利要求5所述的递送装置,其中所述掩味剂选自乙酸纤维素,乙酸丁酸纤维素,乙基纤维素,甲基纤维素及其组合。
16.权利要求5所述的递送装置,其中所述矫味剂选自薄荷油,薄荷醇,留兰香油,香草,肉桂油,冬青油,柠檬油,橙皮油,葡萄油,白柠檬油,葡萄柚油,苹果,杏子香精,丁香油,茴香油,豆蔻油,芫荽油,桉树油,小茴香油,柠檬草油,肉豆蔻油及其组合。
17.权利要求1所述的递送装置,其中所述药物活性组合物的pH在约5至约8的pH范围内。
18.权利要求1所述的递送装置,其中所述药物活性成分包含选自下述组分中的一种或多种:ace抑制剂(例如贝那普利,卡托普利,依那普利,赖诺普利,Moxepril,培哚普利,喹那普利,雷米普利和/或群多普利),成瘾性药物(例如丁丙诺啡,戒酒硫,纳美芬,纳曲酮,大麻二酚,纳呋拉啡,纳曲酮和/或伐尼克兰),α-1肾上腺素能阻滞剂(例如阿夫唑嗪,多沙唑嗪,哌唑嗪,坦洛新和/或特拉唑嗪),ALS药物(例如利鲁唑),阿尔茨海默病药物(例如多奈哌齐,加兰他敏,利凡斯的明和/或美金刚),过敏,解热和抗生素药物(例如别嘌呤醇,氮斯汀,倍氯米松,布地奈德,去氨加压素,氟替卡松,苯肾上腺素,巴比妥酸盐,甲硝唑,卡马西平,西咪替丁,布洛芬,青霉素,阿莫西林,氯唑西林,双氯西林,替卡西林,phenyloin,奎尼丁,链霉素和/或万古霉素),镇痛药和麻醉药(例如氯胺酮,喷他佐辛,丙泊酚,芬太尼,丁丙诺啡,羟考酮,氢可酮和/或纳布啡);氨来诺,苯佐卡因,尿素,过氧化物,制霉菌素,利多卡因和/或毛果芸香碱),血管紧张素II受体阻滞剂(例如坎地沙坦,甲磺酸依普沙坦,奥美沙坦,替米沙汀和/或缬沙坦),抗心律失常药(如腺苷,胺碘酮,阿托品,肾上腺素,美西律,莫雷西嗪,普鲁卡因胺,普罗帕酮,奎尼丁,索他洛尔和/或维拉帕米),抗痉挛和抗胆碱能药(例如莨菪碱,东莨菪碱,达非那星,奥昔布宁,索非那新,托特罗定,格隆铵,莨菪碱,奥昔布宁,丙美卡因,东莨菪碱,异丙嗪,黄酮哌酯,曲司氯铵和/或托特罗定),抗惊厥药(例如卡马西平,氯硝西泮,地西泮,乙琥胺,非尔氨酯,普瑞巴林,左乙拉西坦,拉莫三嗪,劳拉西泮,咪达唑仑,奥卡西平,苯巴比妥,噻加宾,妥吡酯和/或丙戊酸),抗抑郁药(如阿塞那平,安非他酮,丁丙诺啡,西酞普兰,地昔帕明,多塞平,度洛西汀,依他普仑,氟西汀,氟伏沙明,丙米嗪,米氮平,奈法唑酮,去甲替林,去甲替林,舍曲林,曲唑酮和/或文拉法辛),止泻药(例如地芬诺酯,阿托品,loparimide和/或碱式水杨酸铋),抗糖尿病药(例如阿卡波糖,米格列醇,和二甲双胍,glucovance,metaglip,metaglip,罗格列酮,osiglitazone,瑞格列奈,氯磺丙脲,格列美脲,格列本脲,格列吡嗪,妥拉磺脲,甲苯磺丁脲,胰高血糖素,extenatide和/或普兰林肽),抗体和免疫性药物(例如阿达木单抗,阿那白滞素,阿利维A酸,贝卡普勒明,炉甘石,多塞平,氟尿嘧啶,马索罗酚,吡美莫司,他克莫司,金诺芬,硫唑嘌呤,依那西普,羟氯喹,英夫利昔单抗,来氟米特,甲氨蝶呤和/或柳氮磺吡啶),止吐药(例如阿瑞吡坦,多拉司琼,氟哌利多,格拉司琼,甲氧氯普胺,昂丹司琼,丙氯拉嗪,东莨菪碱,异丙嗪和/或曲美苄胺),抗真菌药(例如两性霉素B,阿尼芬净,卡泊芬净,克霉唑氟康唑,氟胞嘧啶,灰黄霉素,伊曲康唑,酮康唑,米卡芬净,制霉菌素,泊沙康唑,特比萘芬,伏立康唑,布替萘芬,环吡酮,克霉唑,enconazole,酮康唑,咪康唑,萘替芬,制霉菌素,奥昔康唑特比萘芬,布替萘芬,环吡酮,克霉唑,益康唑,酮康唑,咪康唑,萘替芬,制霉菌素,奥昔康唑,特比萘芬,克林霉素,甲硝唑,布康唑,克霉唑,咪康唑,特康唑和噻康唑,和/或托萘酯),抗肝炎(例如阿德福韦,恩替卡韦,拉米夫定,聚乙二醇化干扰素α-2a,聚乙二醇化干扰素α-2b和利巴韦林合剂,和/或利巴韦林),抗疱疹药(例如阿昔洛韦,泛昔洛韦,伐昔洛韦,阿昔洛韦,二十二烷醇和/或喷昔洛韦),抗组胺药(例如西替利嗪,地氯雷他定,非索非那定,氯雷他定,氯苯那敏,氯马斯汀,赛庚啶,茶苯海明,苯海拉明,和/或羟嗪),抗高血压(例如贝那普利,卡托普利,依那普利,赖诺普利,莫昔普利,氯沙坦,缬沙坦,阿替洛尔&氯噻酮,比索洛尔,美托洛尔,那多洛尔&苄氟噻嗪,普萘洛尔,噻吗洛尔,氨氯地平&贝那普利,维拉帕米&群多普利,阿米洛利,螺内酯,氨苯蝶啶,可乐定,肼屈嗪,甲基多巴,和/或哌唑嗪&泊利噻嗪),抗高血压药(例如阿利吉轮,阿利吉伦,依前列醇,非诺多泮,肼屈嗪,米诺地尔,硝普盐,酚妥拉明和/或曲前列环素),抗流感药(例如磷酸奥司他韦,金刚乙胺和/或扎那米韦),抗疟疾药,抗原生动物药,杀阿米巴药(例如阿托伐醌,氯喹,双碘喹啉,甲氟喹,伯氨喹,乙胺嘧啶,乙胺嘧啶,pyruvium,磺胺多辛和/或奎宁),抗血小板药物(例如阿昔单抗,双嘧达莫/ASA,阿那格雷,西洛他唑,氯吡格雷,双嘧达莫,eptifabatide,噻氯匹定和/或替罗非班),抗精神病药(例如阿立哌唑,氯丙嗪,氯氮平,氟奋乃静,氟哌啶醇,洛沙平,吗茚酮,金刚烷胺,金刚乙胺和美金刚,奥氮平,奋乃静,匹莫齐特,喹硫平,利培酮,硫利达嗪,替沃噻吨,三氟拉嗪,齐拉西酮,和/或锂),抗痉挛药(例如双环胺,donnatal extentabs,丙美卡因,西甲硅油,莨菪碱,利眠宁胶囊,替加色罗,巴氯芬,carisprodol,环苯扎林,环苯扎林,地西泮,美他沙酮,奥芬那君,和/或酒石酸麦角胺),抗疱疹药(例如阿昔洛韦,泛昔洛韦,伐昔洛韦,二十二烷醇和/或喷昔洛韦),抗高血压药(例如卡托普利,可乐定,依那普利,艾司洛尔,甲磺酸非诺多潘,肼屈嗪,拉贝洛尔,尼卡地平和/或硝酸甘油),镇咳药/祛痰药(例如苯佐那酯和/或愈创甘油醚),特应性皮炎药物(例如吡美莫司和/或他克莫司),抗焦虑药(例如苯二氮杂类和非苯二氮杂类镇静剂,如阿普唑仑,丁螺环酮,利眠宁,氯氮氯硝西泮,地西泮,舒乐安定,eszcpiclone,氟西泮,劳拉西泮,咪达唑仑,奥沙西泮,雷米替胺,替马西泮,三唑仑,扎来普隆和唑吡旦;β阻滞剂,如阿替洛尔,倍他洛尔,比索洛尔,卡维地洛,艾司洛尔,拉贝洛尔,美托洛尔,纳多洛尔,吲哚洛尔,普萘洛尔,索他洛尔和/或噻吗洛尔),胆汁酸螯合剂(例如考来烯胺,考来维仑和/或考来替泊),二膦酸盐(如阿仑膦酸盐,依替膦酸盐,帕米膦酸盐,利塞膦酸盐,替鲁膦酸盐和唑来膦酸,雷洛昔芬和/或特立帕肽),良性前列腺肥大性药物(例如阿夫唑嗪,多沙唑嗪,度他雄胺,非那雄胺,坦洛新和/或特拉唑嗪),钙通道阻滞剂(例如氨氯地平,苄普地尔,地尔硫非洛地平,伊拉地平,尼卡地平,硝苯地平和/或尼索地平),头孢菌素类(例如头孢羟氨苄,头孢唑林,头孢拉定,头孢氨苄,头孢克洛,头孢替坦,头孢西丁,头孢丙烯,头孢呋辛,头孢呋辛,氯碳头孢,头孢地尼,头孢克肟,头孢哌酮,头孢噻肟,头孢泊肟,头孢他啶,头孢布烯,头孢唑肟,和/或头孢吡肟),集落刺激因子(例如达依泊汀α,促红细胞生成素,非格司亭,奥普瑞白介素,聚乙二醇化非格司亭,和/或沙格司亭),皮质类固醇(例如布地奈德,醋酸可的松,地塞米松,氟氢可的松,氢化可的松,甲泼尼龙和泼尼松,aclometasone diproprionate,地奈德,flucinolone acetonide,氢化可的松,二丙酸倍他米松,戊酸倍他米松,氯可托龙匹戊酸酯,去羟米松,氟轻松,氟氢缩松,丙酸氟替卡松,chydrocortisone butyrate,戊酸氢化可的松,莫米松糠酸酯,泼尼卡酯,曲安西龙,安西奈德,二丙酸倍他米松增强剂,二丙酸倍他米松,去羟米松,双醋二氟拉松,氟轻松,醋酸氟轻松,哈西奈德,丙酸氯倍他索,双醋二氟拉松和丙酸卤倍他索,和/或曲安奈德),减充血药(例如苯肾上腺素和/或伪麻黄碱),利尿药(例如乙酰唑胺,阿米洛利,阿米洛利和HCTZ苄氟噻嗪,布美他尼,氯噻嗪,氯噻酮,双氯非那胺,伊普利酮,依他尼酸,呋塞米,氢氯噻嗪,HCTZ/triampterene,氢氟噻嗪,吲达帕胺,醋甲唑胺,甲氯噻嗪,甲氯噻嗪,美托拉宗,泊利噻嗪,螺内酯,螺内酯,HCTZ托塞米,三氯噻嗪,和/或氨苯蝶啶),内分泌药物(例如bromoc cinacalcet cosyntropin,riptine,卡麦角林,降钙素,去氨加压素,亮丙立德,奥曲肽和/或加压素),勃起功能障碍药物(例如西地那非,他达拉非和/或伐地那非),贝特类药(例如氯贝特,非诺贝特和/或吉非贝齐),氟喹诺酮类药物(例如环丙沙星,加替沙星,左氧氟沙星,莫西沙星,诺氟沙星和/或氧氟沙星),胃肠道药物(例如阿洛司琼,英夫利昔单抗,美沙拉嗪,米索前列醇,新霉素,octreotidev,奥沙拉嗪,奥利司他,sucralafate,加压素别嘌呤醇,秋水仙碱,丙磺舒,西咪替丁,法莫替丁,尼扎替丁,雷尼替丁,巴柳氮,布地奈德,英夫利昔单抗,美沙拉嗪,奥沙拉秦,和/或柳氮磺吡啶),干扰素(例如干扰素α-2A,干扰素α-2b,干扰素α-2b和利巴韦林组合包装,干扰素α-N3,干扰素β-1A,干扰素西洛他唑,和/或己酮可可碱),免疫法(例如B型流感嗜血杆菌和乙型肝炎联合疫苗,白喉-破伤风类毒素,甲型肝炎疫苗,乙型肝炎疫苗,流行性感冒疫苗,流感病毒疫苗,莱姆病疫苗,和/或纽莫法23价肺炎球菌疫苗注射液),肝素(例如达肝素,达那肝素,依诺肝素,亭扎肝素,和/或磺达肝素),大环内酯类药物(例如阿奇霉素,克拉霉素和/或红霉素),偏头痛药物(例如阿莫曲普坦,依来曲普坦,夫罗曲普坦,那拉曲坦,利扎曲普坦,舒马曲坦,佐米曲普坦,和/或双氢麦角胺),神经肌肉阻滞剂(如阿曲库铵,顺式阿曲库铵,多库铵,米库氯铵,泮库溴铵,罗库溴铵,琥珀胆碱,维库溴铵,米库氯铵,雷帕库铵,罗库溴铵,琥珀胆碱,阿曲库铵,顺式阿曲库铵,泮库溴铵,维库溴铵,多库铵,哌库溴铵,和/或筒箭毒碱),硝酸盐/酯(例如硝酸异山梨醇酯、单硝酸异山梨糖醇,和/或硝酸甘油),NSAIDs(例如奥湿克,双氯芬酸,依托度酸,吲哚美辛,酮咯酸,舒林酸,tolmentin,二氟尼柳双水杨酯美洛昔康,吡罗昔康,萘丁美酮苯氟布洛芬,布洛芬,酮洛芬,萘普生,奥沙普秦,塞来昔布,罗非昔布,和/或伐地昔布),麻醉剂(例如可待因,芬太尼,氢可酮,氢化吗啡酮,哌替啶美沙酮,吗啡,羟考酮,右丙氧芬,曲马朵,paracetomol,丁丙诺啡,布托啡诺,环丁甲羟氢吗啡,喷他佐辛,纳美芬,纳洛酮,ziconotide哌替啶,和/或吗啡),帕金森疾病疗法(例如金刚烷胺,苯扎托品,溴隐亭,恩托卡朋,培高利特,普拉克索,罗匹尼罗,司来吉兰, 托卡朋,和/或苯海索),质子泵抑制剂(例如埃索美拉唑,兰索拉唑,奥美拉唑,泮托拉唑,和/或雷贝拉唑钠),银屑病药疗法(例如,阿维A、阿来西普,地蒽酚,卡泊三醇,依法珠单抗,和/或他扎罗汀),肺部药物(例如异丙托溴铵、tiotropium、沙丁胺醇、双甲苯喘定、左旋沙丁胺醇、吡布特罗、间羟异丙肾上腺素、福莫特罗、沙美特罗、 倍氯米松、布地奈德、氟尼缩松、氟替卡松、糠酸莫米松、曲安西龙、孟鲁司特、扎鲁司特、色甘酸钠、奈多罗米、乙酰半胱氨酸,和/或氨茶碱/茶碱),HMG COA还原酶抑制剂(例如阿托伐他汀、氟伐他汀、洛伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀,和/或依折麦布),兴奋剂(例如托莫西汀、苄甲苯丙胺、咖啡因、dexmethylphenidate、右旋苯丙胺、安非泼拉酮、哌甲酯、莫达非尼、苯异妥英、phendimetrizine、芬特明和西布曲明),四环素类抗生素(例如多西环素、米诺环素,和/或四环素),泌尿外科药(例如戊聚糖、bethanecol,和/或非那吡啶),血管扩张药和血管加压药(例如甲磺酸非诺多泮、肼屈嗪、奈西利肽、硝酸甘油、多巴酚丁胺、多巴胺、肾上腺素、inaminone、米力农、尼古丁、去甲肾上腺素、苯肾上腺素,和/或血管加压素)。
19.权利要求18所述的递送装置,其中所述活性成分包含纳美芬或其盐。
20.权利要求18所述的递送装置,其中所述纳美芬在所述的活性组合物中的浓度范围为约20%至约60%w/w。
21.权利要求1所述的递送装置,其中所述聚合物膜的粘度为约10,000cP至约35,000cP,所述粘度包括约15,000cP至约25,000cP,以及约18,000cP至约22,000cP。
22.权利要求1所述的递送装置,其中所述聚合物基质包含成膜聚合物和粘膜粘附聚合物。
23.权利要求22所述的递送装置,其中所述成膜聚合物包含水溶性,水溶胀性和/或水蚀性聚合物。
24.权利要求23所述的递送装置,其中所述聚合物基质包含羟丙基甲基纤维素(HPMC),甲基纤维素,羟乙基纤维素(HPC),羟丙基纤维素,聚乙烯吡咯烷酮,羧甲基纤维素钠,聚氧化乙烯(PEO),普鲁蓝,海藻酸,海藻酸钠,聚乙二醇,果胶,黄原胶,黄芪胶,瓜尔豆胶,金合欢胶,阿拉伯胶,槐豆胶,结冷胶,聚丙烯酸,与二乙烯基乙二醇交联的聚丙烯酸,甲基丙烯酸甲酯共聚物,羧基乙烯基共聚物,天然和水解淀粉,A和B型明胶,角叉菜胶或其组合。
25.权利要求1所述的递送装置,其中所述聚合物膜进一步包含渗透促进剂,pH调节剂,掩味剂和矫味剂。
26.权利要求25所述的递送装置,其中所述渗透促进剂选自亲脂性溶剂,表面活性剂,薄荷醇,脂肪酸酯和多元醇中的一种或多种。
27.权利要求25所述的递送装置,其中所述pH调节剂选自磷酸盐,乙酸盐,柠檬酸盐,精氨酸,TRIS和组氨酸缓冲液中的一种或多种。
28.权利要求25所述的递送装置,其中所述药物组合物在表面的pH可以与构成所述膜的聚合物基质的pH不同。
29.权利要求28所述的递送装置,其中所述药物组合物表面上的pH与所述的聚合物基质的pH之间的pH差超过0.3pH单位。
30.权利要求25所述的递送装置,其中所述掩味剂选自乙酸纤维素,乙酸丁酸纤维素,乙基纤维素,甲基纤维素及其组合。
31.权利要求25所述的递送装置,其中所述矫味剂选自薄荷油,薄荷醇,留兰香油,香草,肉桂油,冬青油,柠檬油,橙皮油,葡萄油,白柠檬油,葡萄柚油,苹果,杏子香精,丁香油,茴香油,豆蔻油,芫荽油,桉树油,小茴香油,柠檬草油,肉豆蔻油及其组合。
32.权利要求1所述的递送装置,其进一步包含置于所述的聚合物膜和所述的药物活性组合物之间的中间层,粘合层包含自组装或自聚集部分,其中所述自组装或自聚集部分选自磷脂,胆汁酸,胆盐,纳米血小板结构和可食用粘土中的一种或多种。
33.权利要求32所述的递送装置,其中所述自组装或自聚集部分包含疏水性自组装部分。
34.制备包含药物活性物的经粘膜的递送装置的方法,其包含:
-将聚合物基质和pH调节剂掺合;
-溶解所述掺合物;
-将所述掺合物铸塑在湿的聚合物膜中;
-干燥聚合物膜;
-将药物活性组合物施加到聚合物膜的表面上,其中所述组合物的粘度为约1cP至约100cP;以及
-将具有对其施加的药物活性组合物的聚合物膜加热,以形成包含药物活性物的经粘膜的递送装置。
35.制备包含药物活性物的经粘膜的递送装置的方法,其包含
-将聚合物基质和pH调节剂掺合;
-溶解所述掺合物;
-将所述掺合物铸塑在湿的聚合物膜中;
-将药物活性组合物施加到湿的聚合物膜的表面上,其中所述组合物的粘度为约1cP至约100cP;以及
-将具有对其施加的药物活性组合物的聚合物膜加热,以形成包含药物活性物的经粘膜的递送装置。
36.权利要求34或权利要求35所述的制备方法,其中施加所述药物活性组合物包含通过液滴沉积,喷雾,例如通过电喷雾、超声雾化器、雾化涂层和/或在所述聚合物薄膜上进行超薄网状涂覆工艺将所述的药物活性成分施加到所述膜的表面上。
37.权利要求36所述的制备方法,其中所述药物活性组合物的粘度为约1cP至约50cP。
38.权利要求36所述的制备方法,其中在约50℃至约150℃的温度下进行具有对其施加的活性组合物的聚合物膜的加热。
39.权利要求36所述的制备方法,其中将具有对其施加的活性组合物的聚合物膜加热约3分钟至约10分钟。
40.权利要求34或权利要求35所述的制备方法,其中施加所述药物活性成分包含在所述膜的表面上逐滴沉积所述药物活性成分。
41.权利要求40所述的制备方法,其中所述药物活性组合物的粘度为约20cP至约100cP。
42.权利要求40所述的制备方法,其中当将药物活性组合物的液滴沉积在其上时,所述聚合物膜的温度为约90℃至约150℃。
43.权利要求40所述的制备方法,其中将具有对其施加的活性成分的聚合物膜加热约10分钟至约20分钟。
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PCT/US2019/019150 WO2019165208A1 (en) | 2018-02-22 | 2019-02-22 | Transmucosal film composition and methods of making and using the same |
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JP (1) | JP2021515034A (zh) |
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AU (1) | AU2019224084A1 (zh) |
CA (1) | CA3091443A1 (zh) |
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US11318107B2 (en) * | 2019-02-22 | 2022-05-03 | Avior, Inc. | Pharmaceutical active-containing film delivery device for oral transmucosal administration |
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KR102216578B1 (ko) * | 2019-09-05 | 2021-02-17 | 주식회사 아이큐어비앤피 | 테리파라타이드를 포함하는 경구용 약학 조성물 및 이의 제조방법 |
KR102525213B1 (ko) * | 2021-01-13 | 2023-04-25 | 아주대학교산학협력단 | Qr 코드가 적용된 구강붕해필름 및 3d 프린팅 기술을 이용한 이의 제조방법 |
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US20210085622A1 (en) | 2021-03-25 |
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